NRAS p.Pro185Ser
c.553C>T · rs374061873 · VCV179025
ClinGen expert panel — RASopathy VCEP
Uncertain Significance for RASopathy. Applied ACMG criteria (verbatim):
BP4
Curation rationale (ClinGen, verbatim)
The NM_002524.5:c.553C>T variant in NRAS is a missense variant predicted to cause substitution of proline by serine at amino acid 185 (p.Pro185Ser). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006663 (14/129152 alleles) in the European (non-Finnish) population (Optional: PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.051, which is below the threshold of 0.3, evidence that does not predict a damaging effect on NRAS function (BP4). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: BP4 (ClinGen RASopathy VCEP specifications version 2.3; 12/3/2024)
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.1175 | likely benign |
|---|---|---|
| REVEL | 0.051 | moderately benign-leaning |
| SaProt | LLR -4.47 | tolerated |
| ⇒ AlphaMissense, REVEL and SaProt all call this tolerated. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 6.5 | GERP 1.6, phastCons 1 |
| Regional constraint | o/e 0.62 | unconstrained · MANE · 7,622 bp · p 6.3e-09 · regional, not allelic |
| Overall | ||
| CADD | 20.2 | PHRED · no single calibrated threshold — expert panels disagree |
ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Admixed Americangrpmax | 0.0117% | 8,569 |
| European (non-Finnish) | 0.00975% | 10,258 |
| Remaining individualsnot grpmax-eligible | 0.0064% | 15,620 |
| African / African-American | 0.00134% | 74,904 |
Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.
Variant & gene context
- Gene
- NRAS
- Protein
- p.Pro185Ser
- Coding
- c.553C>T
- MANE Select
- NM_002524
- dbSNP
- rs374061873
- Type
- single nucleotide variant
- Location
- chr1:114708552 (GRCh38)
- Gene constraint
- LOEUF 0.55 · pLI 0.94 · ClinGen HI 0/3 (gnomAD)
- Structure
- AlphaFold pLDDT 92.56 · 36 PDB
- Residue 185
- the 'hypervariable region' region
Similar variants
- NRAS p.Pro185= Likely benign ★ same residue
- NRAS p.Pro185Gln Uncertain significance ★ ⚠ same residue
- NRAS p.Pro185Leu Uncertain significance ★ ⚠ same residue
- NRAS p.Gly12Ser Pathogenic ★★★ same condition
- NRAS p.Gly60Glu Pathogenic ★★★ same condition
- NRAS p.Ile24Asn Likely pathogenic ★★★ same condition
- NRAS p.Thr50Ile Pathogenic ★★★ same condition
- NRAS p.Thr58Ile Pathogenic ★★★ same condition
Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →
Cite Sugi Variant
Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/nras-p-pro185ser (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown